HIV+ patients exhibit more severe and progressive human papillomavirus (HPV) infections than HIV- individuals, and consequently cervical cancer has been designated an HIV-associated malignancy. In addition, HIV+ patients acquire more frequent multi-type infections, and many of these HPV genotypes are infrequently seen in HIV- individuals, and consequently are not targeted by the current HPV vaccines based upon L1 virus-like particles (VLPs). The principal goal of this proposal is to develop a broadly protective HPV vaccine, at low cost, to meet the needs of HIV+ girls and women in the developing world who can neither afford the currently licensed and costly HPV vaccines, nor have access to cytologic screening. A broadly protective HPV vaccine would be particularly helpful in preventing the unusual HPV types and multi-type HPV infections seen in the HIV+ population. Due to the prevalence of infection and the lack of antiviral agents for HPV, development of prophylactic vaccines against HPV is a successful strategy in the prevention of the cervical cancer. There are more than 15 different "oncogenic" types of genital HPV associated with cervical cancer and it is important to protect against all of them. Importantly, we recently discovered that sequences at the amino-terminus of the HPV L2 minor capsid protein elicit broadly cross-neutralizing antibodies and protect animals from diverse papillomavirus types. The development of a vaccine based on the L2 capsid protein could be a single polypeptide produced in bacteria or a single DNA expression vector. Furthermore, L1 capsomeres, the pentameric subunits of VLPs that can be prepared after expression in bacteria, are equally efficacious in eliciting immunity as VLPs, have potentially strong adjuvant properties, and can be complexed/linked with L2 sequences to form a hybrid immunogen. Thus we have several promising approaches for a "broad spectrum" HPV vaccine that can be prepared from bacteria at low cost. We propose to optimize three different approaches for such second generation prophylactic HPV vaccines. SPECIFIC AIM 1 (Dr. R. Roden): Compare candidate L2-based HPV vaccines in an animal challenge model for protection against vaginal challenge with medically significant HPV genotypes. SPECIFIC AIM 2 (Dr. R. Garcea): Determine the optimal formulation of an L1 capsomere- L2 peptide combination vaccine. SPECIFIC AIM 3 (Dr. T.C. Wu): Determine the immunogenicity of polymeric L2 expression vectors or HPV L1-polymeric L2 expression vectors using vaginal challenge in mice vaccinated by in vivo electroporation. The potential of these approaches will be directly compared in an intravaginal HPV challenge model to assess the efficacy of immunization and the longevity of immunity. These projects and PIs are highly interactive to facilitate rapid selection of the optimized vaccine candidates within two years. PUBLIC HEALTH RELEVANCE: HIV+ patients exhibit more severe and progressive human papillomavirus (HPV) infections than HIV- individuals, and consequently cervical cancer has been designated an HIV-associated malignancy. In addition, HIV+ patients more often acquire multi-type infections and many of these HPV genotypes are infrequently seen in HIV- individuals, and consequently are not targeted by the current HPV vaccines. The principal goal of this proposal is to develop a broadly protective HPV vaccine, at low cost, to meet the needs of HIV+ girls and women in the developing world who can neither afford the currently licensed HPV vaccines, nor have access to cytologic screening.